Prostaglandins are a family of biologically active compounds that are found in virtually all tissues and organs. These naturally occurring prostaglandis have extremely complex biological functions (e.g. stimulation of smooth muscles, dilation of smaller arteries and bronchi, lowering blood pressure, etc.). Synthetic prostaglandins are for example clinically used to induce childbirth or abortion, to prevent and treat peptic ulcers, to treat pulmonary hypertension, or in treatment of glaucoma and ocular hypertension.
Prostaglandin F2α (PGF2α-(Z)-7-((1R,2R,3R,5S)-3,5-dihydroxy-2-((S,E)-3-hydroxyoct-1-enyl)cyclopentyl)hept-5-enoic acid)) has the structure:

The PGF2α-derivatives are thus characterized by two hydroxyl groups in cis configuration relative to the cyclopentane ring, and two side chains in a trans configuration relative to each other. Analogs of PGF2α may have a different number of double bonds in the side chains and the substituents along the side chains as well as the length of the side chains may vary. The Z-configured double bond in the α-chain is a common feature in pharmaceutically active PGF2α analogs, whereas the double bond in the ω-chain may be missing (e.g. latanoprost and unoprostone). The carboxylic acid function may be esterified (in particular isopropyl esters proved to be clinically useful e.g. latanoprost and travoprost) or converted into an amide (e.g. bimatoprost).
Examples for PGF2α-derivatives having therapeutic use are latanoprost (general formula (A)), having a saturated ω-chain bearing a phenyl substituent and wherein the carboxylic acid in the α-chain is esterified, travoprost (general formula (B)), containing a trifluoromethylphenyl ether in the ω-chain and wherein the acid function in the α-chain is also esterified, and bimatoprost (general formula (C)), having a phenyl substituent in the ω-chain and wherein the acid function in the α-chain is converted into an amide.

All three compounds shown above are used in the clinic to treat glaucoma and ocular hypertension.
PGF2α-analogs for use in treatment of glaucoma and ocular hypertension are described for example in EP 0 364 417 A1 (Pharmacia AB). In this patent a number of PGF2α-analogs with variations in the ω-chain are described. The synthesis disclosed follows to a large extent the original route of Corey et al. (Corey, E. J.; Weinshenker, N. M.; Schaaf, T. K.; Huber, W. J. Am. Chem. Soc. 1969, 91, 5675-5677; Corey, E. J.; Noyori, R.; Schaaf, T. K. J. Am. Chem. Soc. 1970, 92, 2586-2587.) and is shown in scheme 1 for the preparation of 17-phenyl-18,19,20-trinor-PGF2α-isopropy ester.
The starting material disclosed in EP 0 364 417 A1 is commercially available p-phenyl-benzoyl (PPB) protected Corey lactone 1, which is converted into the corresponding aldehyde 2 by oxidation using DCC/DMSO. Compound 2 is not isolated but reacted in solution with an appropriate phosphonium salt to give intermediate 3. Reduction of the ketone in compound 3 forms the corresponding alcohol 4 as a mixture of diastereomers. After deprotection to form diol 5 the lactone is selectively reduced to the lactol 6 which was purified using column chromatography. A subsequent Wittig reaction forms acid 7 which is converted into the desired product 8 by esterification using isopropyl iodide.

For the synthesis of latanoprost the above shown synthetic route is only altered in that way, that the 13,14-double bond of enone 3 is reduced using 10% Pd/C under hydrogen atmosphere to give the corresponding ketone intermediate with a saturated ω-side chain. The next steps (reduction of the ketone, deprotection, reduction of the lactone, Wittig reaction and esterification) are performed as described above to give latanoprost which was purified using preparative liquid chromatography.
An improved synthesis for such 13,14-dihydro PGF2α-analogs is described in U.S. Pat. No. 5,359,095 (Pharmacia AB). Again, as shown in scheme 2 for the preparation of latanoprost, the disclosed starting material is the PPB-protected Corey lactone 1 which is converted in similar way to the enone 3 as described above. As the original reduction of the ketone only gave 37% yield of the desired 15S-alcohol 9, L-selectride was used as reducing agent, improving the diastereoselectivity of the reduction and increasing the yield of 9 to 60%. It had been found that the allylic alcohol in compound 9 is deoxygenated on hydrogenation of the double bond over palladium catalyst. Therefore, protection of the allylic alcohol seemed to be necessary. This was accomplished by deprotection of compound 9 to afford diol 10 followed by protection of both hydroxyl groups with THP to give compound 11. Reduction of the 13,14-double bond in compound 11 using Pd/C in an hydrogen atmosphere gave compound 12 in almost quantitative yield. Reduction of the lactone moiety in compound 12 afforded lactol 13 in 76% yield. Consecutive Wittig reaction and esterification gave compound 15 in 57% yield after flash chromatography as an oil. Acidic deprotection of the THP groups afforded desired latanoprost in 78% yield. However, this sequence involves two additional steps (protection/deprotection).

In WO 2001/55101 (Finetech) another process for the synthesis of latanoprost is disclosed. In this International patent application a more effective stereoselective reduction of enone 3 is described using (−)-B-chlorodiisopinocamphenylborane [(−)-DIP-Cl] or borane in the presence of CBS-oxazaborolydines to give the desired 15S-alcohol 9 with a diastereomeric excess (de) of 92%. The reduction of the corresponding benzoyl-protected enone using (−)-DIP-Cl has been described previously in U.S. Pat. No. 5,698,733 (Alcon) giving a similar diastereomeric excess.
The free alcohol is protected using the THP group and purified by crystallization. At this stage the unwanted 15R-isomer in the mother liquor may be recycled to 3 using a deprotection-oxidation sequence. The remaining steps to the desired latanoprost are performed similar to the processes described above with modifications concerning the protecting group strategy.
International patent application WO 2006/094294 (Teva) describes another methodology to deplete unwanted 15R-isomer using enzymatic acylation or enzymatic ester hydrolysis.
Patent applications WO 2002/096898 (Resolution Chemicals) and US 2007/0167641 (Chirogate) describe the use of silyl protecting groups in the preparation of PGF2α-analogs.
In the European patent application EP 1721894 A1 (Technopharma) an alternative method for the reduction of the lactone to the lactol using a silane in the presence of a titanocene is described.
The processes described in the state of the art have the drawback that the reduction of the 13-14-double bond is performed using catalytic hydrogenation. This methodology involves the use of hazardous hydrogen gas. The processes disclosed require elaborate protecting group strategies. Furthermore, the isolation of many intermediates is necessary and the process is laborious and less efficient.